Manganese superoxide dismutase mediates anoikis resistance and tumor metastasis in nasopharyngeal carcinoma.

Shuai Li,Xia Yang,Jianxing Ma,Yuling Mao,Weiwei Qi,Jinye Xie,Ti Zhou,Guoquan Gao,Chuanghua Luo,Zhonghan Yang

doi:10.18632/oncotarget.8717

Abstract

Metastatic cancer cells are able to survive the loss of attachment to the extracellular matrix (ECM) by developing resistance to anoikis, a specialized form of apoptosis. Here we investigated resistance to anoikis in nasopharyngeal carcinoma cells (NPC). When detached in culture, the highly metastatic S18 NPC cell line exhibited strong resistance to anoikis, as compared to the poorly metastatic S26 NPC cell line. With loss of attachment, S18 cells had lower levels of reactive oxygen species (ROS) and higher levels of manganese superoxide dismutase (MnSOD), an essential mitochondrial antioxidant enzyme. MnSOD knockdown increased the levels of ROS and diminished resistance to anoikis in S18 cells. Conversely, removal of reactive oxygen species (ROS) using NAC or overexpression of MnSOD in S26 cells induced resistance to anoikis. Blocking β-catenin through RNA interference down-regulated MnSOD expression and enhanced anoikis in S18 cells, while β-catenin overexpression enhanced MnSOD expression and suppressed anoikis in S26 cells. In addition, knockdown of MnSOD in S18 cells reduced colony formation in vitro and ameliorated lung metastasis in vivo. In patients with NPC, MnSOD expression was positively correlated with pathologic tumor stages and negatively correlated with overall survival. These results establish MnSOD as a key mediator of anoikis resistance and tumor metastasis and suggest that β-catenin/MnSOD could be a therapeutic target in NPC.

Highlights

Nasopharyngeal carcinoma (NPC), derived from the epithelial lining of the nasopharrynx, is a commonly occurring cancer with the highest incidence of metastasis among head and neck cancers in southern China and Southeast Asia [1,2,3,4]
When the nasopharyngeal carcinoma cells (NPC) cells were cultured in a three-dimensional model to form clones in Matrigel, the clones generated from S18 cells formed more fully-filled structures when compared with S26 cells (Figure 1D)
Since manganese superoxide dismutase (MnSOD) and catalase are key antioxidant enzymes involved in scavenging reactive oxygen species (ROS), we examined the protein levels of MnSOD and catalase in NPC cells grown in suspension

Summary

Introduction

Nasopharyngeal carcinoma (NPC), derived from the epithelial lining of the nasopharrynx, is a commonly occurring cancer with the highest incidence of metastasis among head and neck cancers in southern China and Southeast Asia [1,2,3,4]. Distant relapse remains the major cause of treatment failure in NPC [5], and the molecular mechanisms underlying NPC metastasis are poorly understood. In order to provide a basis for the development of novel therapeutics for NPC, it is crucial to obtain a better understanding of the molecular mechanisms used by cancer cells to facilitate their survival during metastasis. While there are many abnormal features of metastatic cancer cells, resistance to anoikis is interesting as it enables cell survival with loss of attachment to the extracellular matrix (ECM) [6, 7]. Metastatic cancer cells develop anoikis resistance by www.impactjournals.com/oncotarget triggering several signaling pathways [6, 8, 9], including the production of reactive oxygen species (ROS) and activation of mitochondrial metabolism [10, 11]. Energy deficiency (diminished ATP levels) caused by ECM detachment can reduce the viability of breast cancer cells [11]

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Results

Conclusion